Hansson, O;
Kumar, A;
Janelidze, S;
Stomrud, E;
Insel, PS;
Blennow, K;
Zetterberg, H;
... Mattsson-Carlgren, N; + view all
(2022)
The genetic regulation of protein expression in cerebrospinal fluid.
EMBO Molecular Medicine
, Article e16359. 10.15252/emmm.202216359.
(In press).
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Abstract
Studies of the genetic regulation of cerebrospinal fluid (CSF) proteins may reveal pathways for treatment of neurological diseases. 398 proteins in CSF were measured in 1,591 participants from the BioFINDER study. Protein quantitative trait loci (pQTL) were identified as associations between genetic variants and proteins, with 176 pQTLs for 145 CSF proteins (P < 1.25 × 10−10, 117 cis-pQTLs and 59 trans-pQTLs). Ventricular volume (measured with brain magnetic resonance imaging) was a confounder for several pQTLs. pQTLs for CSF and plasma proteins were overall correlated, but CSF-specific pQTLs were also observed. Mendelian randomization analyses suggested causal roles for several proteins, for example, ApoE, CD33, and GRN in Alzheimer's disease, MMP-10 in preclinical Alzheimer's disease, SIGLEC9 in amyotrophic lateral sclerosis, and CD38, GPNMB, and ADAM15 in Parkinson's disease. CSF levels of GRN, MMP-10, and GPNMB were altered in Alzheimer's disease, preclinical Alzheimer's disease, and Parkinson's disease, respectively. These findings point to pathways to be explored for novel therapies. The novel finding that ventricular volume confounded pQTLs has implications for design of future studies of the genetic regulation of the CSF proteome.
| Type: | Article |
|---|---|
| Title: | The genetic regulation of protein expression in cerebrospinal fluid |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.15252/emmm.202216359 |
| Publisher version: | https://doi.org/10.15252/emmm.202216359 |
| Language: | English |
| Additional information: | License: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | Mendelian randomization, biomarkers, cerebrospinal fluid, genetic regulation, pQTL |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10162445 |
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